The V_H gene repertoire of splenic B cells and somatic hypermutation in systemic lupus erythematosus

In systemic lupus erythematosus (SLE) it has been hypothesized that self-reactive B cells arise from virgin B cells that express low-affinity, nonpathogenic germline V genes that are cross-reactive for self and microbial antigens, which convert to high-affinity autoantibodies via somatic hypermutation. The aim of the present study was to determine whether the V<sub>H</sub> family repertoire and pattern of somatic hypermutation in germinal centre (GC) B cells deviates from normal in SLE. Rearranged immunoglobulin V<sub>H</sub> genes were cloned and sequenced from GCs of a SLE patient's spleen. From these data the GC V gene repertoire and the pattern of somatic mutation during the proliferation of B-cell clones were determined. The results highlighted a bias in V<sub>H</sub>5 gene family usage, previously unreported in SLE, and under-representation of the V<sub>H</sub>1 family, which is expressed in 20–30% of IgM+ B cells of healthy adults and confirmed a defect in negative selection. This is the first study of the splenic GC response in human SLE

Domain variance and superstructure across the antiferroelectric/ferroelectric phase boundary in Pb1−1.5xLax(Zr0.9TiM0.1)O3

Transmission electron microscopy, x-ray diffraction, relative permittivity as a function of temperature, and polarization versus field loops were used to study the antiferroelectric/ferroelectric (AFE/FE) phase boundary in Pb1−1.5xLaxZr0.9Ti0.1O3 (PLZT, 100x/90/10) ceramics. X-ray diffraction and electrical measurements indicated a FE rhombohedral (R) to AFE tetragonal (T) phase transition between PLZT 2/90/10 and 4/90/10. Both phases exhibited superstructure reflections in electron-diffraction patterns at 1⁄2{hkl} positions consistent with rotations of the octahedra in antiphase. Previously, neutron diffraction suggested that the FER has an a−a−a− tilt system (Glazer notation), in agreement with its macroscopic symmetry. By analogy, it is proposed that the AFET phase has an a0a0c− tilt system. The AFE phase was also characterized by incommensurate superstructure along pseudocubic 〈110〉p directions, whereas the FE phase had extra commensurate superlattice reflections at 1⁄2{hk0}p positions. 1⁄2{hk0}p reflections are forbidden in both tilt systems, but their presence is explained by Pb ion displacements averaged along 〈111〉 but with short coherence antiparallel components along 〈110〉 directions. The antiparallel Pb displacements are coupled to an a−b−b− (a ≈ b) monoclinic tilt system in the vicinity of the AFE/FE boundary

The nonperturbative origin of delta-function singularity in the chirally-odd twist-3 distribution function e(x)

We analytically prove that the existence of the delta-function singularity in the chirally-odd twist-3 distribution $e(x)$ of the nucleon is inseparably connected with the nonvanishing quark condensate as a signal of the spontaneous chiral symmetry breaking of the QCD vacuum. This singularity in $e(x)$, which would be observed as a sizable violation of the 1st moment sum rule, is then interpreted as giving a very rare case that the nontrivial vacuum structure of QCD manifests in an observable of a localized QCD excitation, i.e. the nucleon.Comment: 9 pages, 1 eps-figur

Antigen-driven clonal proliferation of B cells within the target tissue of an autoimmune disease: the salivary glands of patients with Sjögren's syndrome

Structures resembling germinal centers are seen in the salivary glands of patients with Sjögren's syndrome, but it is not known whether the microenvironment of these cell clusters is sufficient for the induction of a germinal center response. Therefore, we cloned and sequenced rearranged Ig V genes expressed by B cells isolated from sections of labial salivary gland biopsies from two Sjögren's syndrome patients. Rearranged V genes from B cells within one cell cluster were polyclonal and most had few somatic mutations. Two adjacent clusters from another patient each contained one dominant B cell clone expressing hypermutated V genes. None of the rearranged V genes was found in both clusters, suggesting that cells are unable to migrate out into the surrounding tissue and seed new clusters. The ratios of replacement to silent mutations in the framework and complementarity determining regions suggest antigen selection of high-affinity mutants. These results show that an antigen-driven, germinal center-type B cell response is taking place within the salivary glands of Sjögren's syndrome patients. In view of the recent demonstration of a germinal center response within the rheumatoid synovial membrane and the existence of similar structures in the target tissues of other autoimmune. diseases, we propose that germinal center- type responses can be induced in the nonlymphoid target tissues of a variety of autoimmune diseases

Performance of a Functionalised Polymer-Coated Silica at Treating Uranium Contaminated Groundwater from a Hungarian Mine Site

The performance of an active material for treating uranium contaminated groundwater within a permeable reactive barrier (PRB) is reported. This material, called PANSIL, has a tailored ligand system that selectively removes the uranyl (UO22+) cation from solution. The active uranyl ligand in PANSIL is a polyacryloamidoxime resin derived from polyacrylonitrile, which is deposited from solution onto the surface of quartz sand to form a thin film coating. PANSIL is effective at sequestering cationic and neutral uranyl species when the solution pH is above 4, due to the stability of the polyacryloamidoxime-uranyl complex formed. However the rate of sequestration decreases rapidly when the pH exceeds about 8 where neutral uranyl species are present only at very low concentrations. It can preferentially sequester UO22+ in the presence of typical divalent groundwater cations. In mildly alkaline conditions the sequestration performance in groundwater is sensitive to the concentration of uranyl complexing ligands, such as bicarbonate. Such behaviour has important consequences for PRB design as it will determine the barrier thickness required to treat a particular groundwater flow rate

The chirally-odd twist-3 distribution function e(x) in the chiral quark-soliton model

The chirally-odd twist-3 nucleon distribution e(x) is studied in the large-Nc limit in the framework of the chiral quark-soliton model at a low normalization point of about 0.6 GeV. The remarkable result is that in the model e(x) contains a delta-function-type singularity at x=0. The regular part of e(x) is found to be sizeable at the low scale of the model and in qualitative agreement with bag model calculations.Comment: 16 pages, 6 figures, revtex, Ref.[50] and footnote 3 adde

Immune Responses in Human Necatoriasis: Association between Interleukin-5 Responses and Resistance to Reinfection

Cytokine and proliferative responses to Necator americanus infection were measured in a treatment-reinfection study of infected subjects from an area of Papua New Guinea where N. americanus is highly endemic. Before treatment, most subjects produced detectable interleukin (IL)4 (97%), IL-5 (86%), and interferon (IFN)-γ(64%) in response to adult N. americanus antigen. Pretreatment IFN-γ responses were negatively associated with hookworm burden, decreasing by 18 pg/mL for each increase of 1000 eggs/gram (epg) (n = 75; P < .01). Mean IFN-γ responses increased significantly after anthelmintic treatment, from 166 to 322 pg/mL (n = 42; P < .01). The intensity of reinfection was significantly negatively correlated with pretreatment IL-5 responses, decreasing by 551 epg for each 100 pg/mL increase in production of IL-5 (n = 51; P < .01). These data indicate that there is a mixed cytokine response in necatoriasis, with worm burdenassociated suppression of IFN-γ responses to adult N. americanus antigen. Resistance to reinfection is associated with the parasite-specific IL-5 response

Higher Derivative Operators from Transmission of Supersymmetry Breaking on S_1/Z_2

We discuss the role that higher derivative operators play in field theory orbifold compactifications on S_1/Z_2 with local and non-local (Scherk-Schwarz) breaking of supersymmetry. Integrating out the bulk fields generates brane-localised higher derivative counterterms to the mass of the brane (or zero-mode of the bulk) scalar field, identified with the Higgs field in many realistic models. Both Yukawa and gauge interactions are considered and the one-loop results found can be used to study the ``running'' of the scalar field mass with respect to the momentum scale in 5D orbifolds. In particular this allows the study of the behaviour of the mass under UV scaling of the momentum. The relation between supersymmetry breaking and the presence of higher derivative counterterms to the mass of the scalar field is investigated. This shows that, regardless of the breaking mechanism, (initial) supersymmetry cannot, in general, prevent the emergence of such operators. Some implications for phenomenology of the higher derivative operators are also presented.Comment: 29 pages, LaTeX. Added Section 4 ("Phenomenological implications: living with ghosts?") and Appendix

Distinct forms of synaptic inhibition and neuromodulation regulate calretinin positive neuron excitability in the spinal cord dorsal horn

The dorsal horn (DH) of the spinal cord contains a heterogenous population of neurons that process incoming sensory signals before information ascends to the brain. We have recently characterized calretinin-expressing (CR+) neurons in the DH and shown that they can be divided into excitatory and inhibitory subpopulations. The excitatory population receives high-frequency excitatory synaptic input and expresses delayed firing action potential discharge, whereas the inhibitory population receives weak excitatory drive and exhibits tonic or initial bursting discharge. Here, we characterize inhibitory synaptic input and neuromodulation in the two CR+ populations, in order to determine how each is regulated. We show that excitatory CR+ neurons receive mixed inhibition from GABAergic and glycinergic sources, whereas inhibitory CR+ neurons receive inhibition, which is dominated by glycine. Noradrenaline and serotonin produced robust outward currents in excitatory CR+ neurons, predicting an inhibitory action on these neurons, but neither neuromodulator produced a response in CR+ inhibitory neurons. In contrast, enkephalin (along with selective mu and delta opioid receptor agonists) produced outward currents in inhibitory CR+ neurons, consistent with an inhibitory action but did not affect the excitatory CR+ population. Our findings show that the pharmacology of inhibitory inputs and neuromodulator actions on CR+ cells, along with their excitatory inputs can define these two subpopulations further, and this could be exploited to modulate discrete aspects of sensory processing selectively in the DH

Evidence against AMPA receptor-lacking glutamatergic synapses in the superficial dorsal horn of the rat spinal cord

Pure NMDA receptor (NMDAr)-mediated EPSCs, thought to correspond to "silent" glutamatergic synapses that lack AMPA receptors (AMPArs), have been observed in superficial spinal dorsal horn of neonatal but not adult rats. Recent anatomical studies suggest that AMPArs are present at virtually all glutamatergic synapses in this region in adults. We used antigen retrieval to examine colocalization of AMPArs and PSD-95 (a marker for glutamatergic synapses) in laminae I–II of neonatal and adult rats. We found a high degree of colocalization in all cases, which suggests that AMPArs are present in the great majority of glutamatergic synapses even in neonatal animals. We therefore reexamined evidence for silent synapses by performing blind whole-cell recordings from superficial dorsal horn neurons in slices from neonatal or adult rats, with focal stimulation to activate glutamatergic synapses. On some occasions in both neonatal (10 of 109, 9%) and adult (9 of 77, 12%) slices, NMDAr-mediated EPSCs were observed when the holding potential was raised to +50 mV at a stimulus strength that had failed to evoke AMPAr-mediated EPSCs. However, in all cases tested, AMPAr-mediated EPSCs were then observed when the cell was returned to –70 mV; this and other properties of the EPSCs suggest that they do not represent genuine silent synapses. When compared with previous findings, our results indicate that the appearance of silent synapses depends on experimental protocol. This suggests that pure NMDAr-mediated EPSCs seen in previous studies do not correspond to AMPAr-lacking synapses but result from another mechanism, for example, loss of labile AMPArs from recently formed synapses